This invention relates to 6,7-benzomorphan derivatives. More specifically, it relates to a new process for producing 6,7-benzomorphan derivatives starting from aromatic aminoketones through several steps of reactions and through several intermediates. Most of the intermediates are new compounds. 6,7-benzomorphan derivatives which include pentazocine, phenazocine and cyclazocine are known to have an unaddictive analgesic activity.
6,7-BENZOMORPHAN DERIVATIVES WHICH ARE SUBJECT OF THE PRESENT INVENTION ARE REPRESENTED BY THE FORMULA ##SPC1##
Wherein R.sub.1 represents a hydrogen atom, a hydroxy group, alkyl group preferably having 1 to 4 carbon atoms, such as a methyl, ethyl, isopropyl or n-butyl group, alkoxy group preferably having 1 to 4 carbon atoms, such as a methoxy, ethoxy, isopropoxy or n-butoxy group, benzyloxy group or acyloxy group preferably having 1 to 4 carbon atoms, such as a formyloxy, acetoxy, n-propionyloxy or isobutyryloxy group; R.sub.2 represents a hydrogen atom, an alkyl group preferably having 1 to 8 carbon atoms, such as a methyl, ethyl, n-propyl, isobutyl, n-amyl, n-hexyl, n-heptyl or n-octyl group, substituted alkyl group (alkyl group preferably having 1 to 8 carbon atoms), the substituent being a phenyl group (for example, a benzyl or phenethyl group), benzoyl group, ##SPC2##
Group, =0 group (for example, a 3-methyl carbonylpropyl group) or ##EQU1## group (for example, a ##EQU2## group), CYCLOALKYL GROUP PREFERABLY HAVING 3 TO 6 CARBON ATOMS, SUCH AS A CYCLOPROPYL, CYCLOBUTYL, CYCLOPENTYL OR CYCLOHEXYL GROUP, CYCLOALKYLALKYL GROUP PREFERABLY HAVING 4 TO 8 CARBON ATOMS, SUCH AS A CYCLOPROPYLMETHYL, CYCLOBUTYLETHYL, CYCLOPENTYLMETHYL, CYCLOHEXYLMETHYL OR 3-CYCLOHEXYLPROPYL GROUP, ALKENYL GROUP PREFERABLY HAVING 3 TO 8 CARBON ATOMS, SUCH AS AN ALLYL, 2-METHYL-2PROPENYL, 2-BUTENYL, 3-METHYL-2-BUTENYL OR 3-METHYL-3-BUTENYL GROUP OR SUBSTITUTED ALLKENYL GROUP (ALKENYL GROUP PREFERABLY HAVING 3 TO 8 CARBON ATOMS), THE SUBSTITUENT BEING A HALOGENE ATOM (FOR EXAMPLE, A 3-CHLORO-2-PROPENYL, 3-BROMO-2-PROPENYL OR 2,3-DICHLORO-2-PROPENYL GROUP); AND R.sub.3 and R.sub.4, which may be the same or different, represent alkyl groups preferably having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl or isobutyl groups.
Heretofore, there have been many reports on the processes for the preparation of 6,7-benzomorphan derivatives. These processes may be classified into four main groups of processes.
The first method employs 3,4-disubstituted pyridines as the starting material, which are converted through several steps into 2-benzyl-1,2,3,4-tetrahydropyridine derivatives and cyclized into 6,7-benzomorphan derivatives [J. Org. Chem., 24, 1432 (1959) and J. Heterocyclic Chem., 6, 43 (1959)].
The second method starts from 4-phenylpyridines. The compounds are converted into 2,4-diaxial compounds and followed by cyclization and reduction [J. Am. Chem. Soc., 90, 1064 (1968)].
The third method comprises cyclizing and reducing 2-bromo-4-(2-amino)ethyl-1-ketotetrahydronaphthalene derivatives or 1-(2-amino)ethyl-3-bromo-2-ketotetrahydronaphthalene derivatives prepared from .alpha. or .beta.-tetralone derivatives through several intermediates [J. Chem Soc., 1947, 399 and Synthetic Analgetics, Part IIB, p. 115, Pergamon Press Ltd., Oxford (1966)].
In the fourth method, .gamma.,.delta.-unsaturated alkylamines prepared from ketones and cyanoacetic acid esters are condensed with phenylacetaldehyde derivatives. The resultant 2-benzylpiperidine derivatives are cyclized into 6,7-benzomorphan derivatives [British Pat. No. 1,079,489 and J. Heterocyclic Chem., 8, 769 (1971)].
These four method are schematically illustrated below; ##SPC3## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have the same significance as defined above.
However, any of these prior art processes has its own disadvantages. More specifically, in the first method, some of the intermediates are unstable. The Grignard's reaction and Stevens rearrangement reaction involved in this method result only low yields. Further, many complicated reactions are involved in the intermediate steps. Thus, the method is not practical for industrial purpose. In accordance with the second method, it is very difficult to prepare 6,7-benzomorphan derivatives having substituents at the 5 and 9 positions, which are clinically very important. The third method employs .alpha.- or .beta.-tetralone as the starting materials, and has a difficulty in preparing 6,7-benzomorphan derivatives having a substituent at the 9 position. Further, in the fourth method, many complicated steps are involved in the preparation of the intermediate, .gamma.,.delta.-unsaturated alkylamines.
In an attempt to improve the disadvantages of the prior art processes, the present inventors have made studies on the preparation of 6,7-benzomorphan derivatives. As the result, they have developed a new process, quite different from the known processes, where 6,7-benzomorphan derivatives are prepared through a series of reactions starting from aromatic aminoketones which are prepared from phenylalanine or its derivatives.
The present invention provides an advantageous process for the preparation of 6,7-benzomorphan derivatives in that the starting material is available at a low cost. Moreover, according to the present invention, 6,7-benzomorphan derivatives having various substituents at the 2, 5 and 9 positions can be obtained and the intermediates are free from unstability.
The present invention also provides a process for producing 2-benzyl-1,2,5,6-tetrahydropyridine derivatives. The compounds which are known as an intermediate in the above-mentioned first prior art method are prepared from one of the intermediates of the present process.